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Abstract:

The present invention relates to novel cycloalkyl-hydroxyl compounds,
compositions comprising hydroxyl compounds, and methods useful for
treating and preventing a variety of diseases and conditions such as, but
not limited to aging, Alzheimer's Disease, cancer, cardiovascular
disease, diabetic nephropathy, diabetic retinopathy, a disorder of
glucose metabolism, dyslipidemia, dyslipoproteinemia, hypertension,
impotence, inflammation, insulin resistance, lipid elimination in bile,
obesity, oxysterol elimination in bile, pancreatitis, Parkinson's
disease, a peroxisome proliferator activated receptor-associated
disorder, phospholipid elimination in bile, renal disease, septicemia,
Syndrome X, thrombotic disorder. Compounds and methods of the invention
can also be used to modulate C reactive protein or enhance bile
production in a patient. In certain embodiments, the compounds,
compositions, and methods of the invention are useful in combination
therapy with other therapeutics, such as hypocholesterolemic and
hypoglycemic agents.

Claims:

1. A compound of formula I: ##STR00026## or a pharmaceutically
acceptable salt, hydrate, solvate or a mixture thereof, wherein: (a) each
occurrence of m is independently an integer ranging from 0 to 5; (b) each
occurrence of n is independently an integer ranging from 3 to 7; (c) X is
(CH2)z or Ph, wherein z is an integer from 0 to 4; (d) each
occurrence of R1 and R2 is independently
(C1-C6)alkyl, (C2-C6)alkenyl,
(C2-C6)alkynyl, phenyl, benzyl, or R1 and R2 and the
carbon to which they are both attached are taken together to form a
(C3-C7)cycloakyl group; (e) each occurrence of R11 and
R12 and the carbon to which they are both attached are taken
together to form a (C3-C7)cycloakyl group; (f) each occurrence
of Y1 and Y2 is independently (C1-C6)alkyl, OH, COOH,
COOR3, SO3H, ##STR00027## ##STR00028## wherein: (i) R3
is (C1-C6)alkyl, (C2-C6)alkenyl,
(C2-C6)alkynyl, phenyl, or benzyl and is unsubstituted or
substituted with one or more halo, OH, (C1-C6)alkoxy, or phenyl
groups, (ii) each occurrence of R4 is independently H,
(C1-C6)alkyl, (C2-C6)alkenyl, or
(C2-C6)alkynyl and is unsubstituted or substituted with one or
two halo, OH, C1-C6 alkoxy, or phenyl groups; and (iii) each
occurrence of R5 is independently H, (C1-C6)alkyl,
(C2-C6)alkenyl, or (C2-C6)alkynyl.

2. The compound of claim 1, wherein each occurrence of Y1 and
Y2 is independently OH, COOR3, or COOH.

3. The compound of claim 1, wherein m is 0.

4. The compound of claim 1, wherein m is 1.

5. The compound of claim 1, wherein n is 4.

6. The compound of claim 1, wherein n is 5.

7. The compound of claim 1, wherein X is (CH2)z and z is 0.

8. The compound of claim 1, wherein each occurrence of R1 and
R2 and the carbon to which they are both attached are taken together
to form a (C3-C7)cycloakyl group.

9. The compound of claim 1, wherein Y1 and Y2 are each
independently (C1-C6)alkyl.

10. The compound of claim 1, wherein Y and Y2 are each methyl.

11-57. (canceled)

Description:

[0001] This application claims the benefit of U.S. Provisional Application
No. 60/441,795, filed Jan. 23, 2003, which is incorporated herein by
reference in its entirety.

[0003] Obesity, hyperlipidemia, and diabetes have been shown to play a
causal role in atherosclerotic cardiovascular diseases, which currently
account for a considerable proportion of morbidity in Western society.
Further, one human disease, termed "Syndrome X" or "Metabolic Syndrome",
is manifested by defective glucose metabolism (insulin resistance),
elevated blood pressure (hypertension), and a blood lipid imbalance
(dyslipidemia). See e.g. Reaven, 1993, Annu. Rev. Med. 44:121-131.

[0004] The evidence linking elevated serum cholesterol to coronary heart
disease is overwhelming. Circulating cholesterol is carried by plasma
lipoproteins, which are particles of complex lipid and protein
composition that transport lipids in the blood. Low density lipoprotein
(LDL) and high density lipoprotein (HDL) are the major
cholesterol-carrier proteins. LDL is believed to be responsible for the
delivery of cholesterol from the liver, where it is synthesized or
obtained from dietary sources, to extrahepatic tissues in the body. The
term "reverse cholesterol transport" describes the transport of
cholesterol from extrahepatic tissues to the liver, where it is
catabolized and eliminated. It is believed that plasma HDL particles play
a major role in the reverse transport process, acting as scavengers of
tissue cholesterol. HDL is also responsible for the removal of
non-cholesterol lipid, oxidized cholesterol and other oxidized products
from the bloodstream.

[0005] Atherosclerosis, for example, is a slowly progressive disease
characterized by the accumulation of cholesterol within the arterial
wall. Compelling evidence supports the belief that lipids deposited in
atherosclerotic lesions are derived primarily from plasma apolipoprotein
B (apo B)-containing lipoproteins, which include chylomicrons, very low
density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and
LDL. The apo B-containing lipoprotein, and in particular LDL, has
popularly become known as the "bad" cholesterol. In contrast, HDL serum
levels correlate inversely with coronary heart disease. Indeed, high
serum levels of HDL are regarded as a negative risk factor. It is
hypothesized that high levels of plasma HDL are not only protective
against coronary artery disease, but may actually induce regression of
atherosclerotic plaque (e.g., see Badimon et al., 1992, Circulation
86:(Suppl. 11)86-94; Dansky and Fisher, 1999, Circulation 100:1762 3.).
Thus, HDL has popularly become known as the "good" cholesterol.

2.1 Cholesterol Transport

[0006] The fat-transport system can be divided into two pathways: an
exogenous one for cholesterol and triglycerides absorbed from the
intestine and an endogenous one for cholesterol and triglycerides
entering the bloodstream from the liver and other non-hepatic tissue.

[0007] In the exogenous pathway, dietary fats are packaged into
lipoprotein particles called chylomicrons, which enter the bloodstream
and deliver their triglycerides to adipose tissue for storage and to
muscle for oxidation to supply energy. The remnant of the chylomicron,
which contains cholesteryl esters, is removed from the circulation by a
specific receptor found only on liver cells. This cholesterol then
becomes available again for cellular metabolism or for recycling to
extrahepatic tissues as plasma lipoproteins.

[0008] In the endogenous pathway, the liver secretes a large,
very-low-density lipoprotein particle (VLDL) into the bloodstream. The
core of VLDL consists mostly of triglycerides synthesized in the liver,
with a smaller amount of cholesteryl esters either synthesized in the
liver or recycled from chylomicrons. Two predominant proteins are
displayed on the surface of VLDL, apolipoprotein B-100 (apo B-100) and
apolipoprotein E (apo E), although other apolipoproteins are present,
such as apolipoprotein CIII (apo CIII) and apolipoprotein CII (apo CII).
When VLDL reaches the capillaries of adipose tissue or of muscle, its
triglyceride is extracted. This results in the formation of a new kind of
particle called intermediate-density lipoprotein (IDL) or VLDL remnant,
decreased in size and enriched in cholesteryl esters relative to a VLDL,
but retaining its two apoproteins.

[0009] In human beings, about half of the IDL particles are removed from
the circulation quickly, generally within two to six hours of their
formation. This is because IDL particles bind tightly to liver cells,
which extract IDL cholesterol to make new VLDL and bile acids. The IDL
not taken up by the liver is catabolized by the hepatic lipase, an enzyme
bound to the proteoglycan on liver cells. Apo E dissociates from IDL as
it is transformed to LDL. Apo B-100 is the sole protein of LDL.

[0010] Primarily, the liver takes up and degrades circulating cholesterol
to bile acids, which are the end products of cholesterol metabolism. The
uptake of cholesterol-containing particles is mediated by LDL receptors,
which are present in high concentrations on hepatocytes. The LDL receptor
binds both apo E and apo B-100 and is responsible for binding and
removing both IDL and LDL from the circulation. In addition, remnant
receptors are responsible for clearing chylomicrons and VLDL remnants
(i.e., IDL). However, the affinity of apo E for the LDL receptor is
greater than that of apo B-100. As a result, the LDL particles have a
much longer circulating life span than IDL particles; LDL circulates for
an average of two and a half days before binding to the LDL receptors in
the liver and other tissues. High serum levels of LDL, the "bad"
cholesterol, are positively associated with coronary heart disease. For
example, in atherosclerosis, cholesterol derived from circulating LDL
accumulates in the walls of arteries. This accumulation forms bulky
plaques that inhibit the flow of blood until a clot eventually forms,
obstructing an artery and causing a heart attack or stroke.

[0011] Ultimately, the amount of intracellular cholesterol liberated from
the LDL controls cellular cholesterol metabolism. The accumulation of
cellular cholesterol derived from VLDL and LDL controls three processes.
First, it reduces the ability of the cell to make its own cholesterol by
turning off the synthesis of HMGCoA reductase, a key enzyme in the
cholesterol biosynthetic pathway. Second, the incoming LDL-derived
cholesterol promotes storage of cholesterol by the action of cholesterol
acyltransferase ("ACAT"), the cellular enzyme that converts cholesterol
into cholesteryl esters that are deposited in storage droplets. Third,
the accumulation of cholesterol within the cell drives a feedback
mechanism that inhibits cellular synthesis of new LDL receptors. Cells,
therefore, adjust their complement of LDL receptors so that enough
cholesterol is brought in to meet their metabolic needs, without
overloading (for a review, see Brown & Goldstein, in The Pharmacological
Basis Of Therapeutics, 8th Ed., Goodman & Gilman, Pergamon Press, New
York, 1990, Ch. 36, pp. 874-896).

[0012] High levels of apo B-containing lipoproteins can be trapped in the
subendothelial space of an artery and undergo oxidation. The oxidized
lipoprotein is recognized by scavenger receptors on macrophages. Binding
of oxidized lipoprotein to the scavenger receptors can enrich the
macrophages with cholesterol and cholesteryl esters independently of the
LDL receptor. Macrophages can also produce cholesteryl esters by the
action of ACAT. LDL can also be complexed to a high molecular weight
glycoprotein called apolipoprotein(a), also known as apo(a), through a
disulfide bridge. The LDL-apo(a) complex is known as Lipoprotein(a) or
Lp(a). Elevated levels of Lp(a) are detrimental, having been associated
with atherosclerosis, coronary heart disease, myocardial infarction,
stroke, cerebral infarction, and restenosis following angioplasty.

2.2 Reverse Cholesterol Transport

[0013] Peripheral (non-hepatic) cells predominantly obtain their
cholesterol from a combination of local synthesis and uptake of preformed
sterol from VLDL and LDL. Cells expressing scavenger receptors, such as
macrophages and smooth muscle cells, can also obtain cholesterol from
oxidized apo B-containing lipoproteins. In contrast, reverse cholesterol
transport (RCT) is the pathway by which peripheral cell cholesterol can
be returned to the liver for recycling to extrahepatic tissues, hepatic
storage, or excretion into the intestine in bile. The RCT pathway
represents the only means of eliminating cholesterol from most
extrahepatic tissues and is crucial to the maintenance of the structure
and function of most cells in the body.

[0014] The enzyme in blood involved in the RCT pathway,
lecithin:cholesterol acyltransferase (LCAT), converts cell-derived
cholesterol to cholesteryl esters, which are sequestered in HDL destined
for removal. LCAT is produced mainly in the liver and circulates in
plasma associated with the HDL fraction. Cholesterol ester transfer
protein (CETP) and another lipid transfer protein, phospholipid transfer
protein (PLTP), contribute to further remodeling the circulating HDL
population (see for example Bruce et al., 1998, Annu. Rev. Nutr. 18:297
330). PLTP supplies lecithin to HDL, and CETP can move cholesteryl esters
made by LCAT to other lipoproteins, particularly apoB-containing
lipoproteins, such as VLDL. HDL triglycerides can be catabolized by the
extracellular hepatic triglyceride lipase, and lipoprotein cholesterol is
removed by the liver via several mechanisms.

[0015] Each HDL particle contains at least one molecule, and usually two
to four molecules, of apolipoprotein A I (apo A I). Apo A I is
synthesized by the liver and small intestine as preproapolipoprotein,
which is secreted as a proprotein that is rapidly cleaved to generate a
mature polypeptide having 243 amino acid residues. Apo A I consists
mainly of a 22 amino acid repeating segment, spaced with helix-breaking
proline residues. Apo A I forms three types of stable structures with
lipids: small, lipid-poor complexes referred to as pre-beta-1 HDL;
flattened discoidal particles, referred to as pre-beta-2 HDL, which
contain only polar lipids (e.g., phospholipid and cholesterol); and
spherical particles containing both polar and nonpolar lipids, referred
to as spherical or mature HDL (HDL3 and HDL2). Most HDL in the
circulating population contains both apo A I and apo A II, a second major
HDL protein. This apo A I- and apo A II-containing fraction is referred
to herein as the AI/AII-HDL fraction of HDL. But the fraction of HDL
containing only apo A I, referred to herein as the AI HDL fraction,
appears to be more effective in RCT. Certain epidemiologic studies
support the hypothesis that the AI-HDL fraction is antiartherogenic
(Parra et al., 1992, Arterioscler. Thromb. 12:701-707; Decossin et al.,
1997, Eur. J. Clin. Invest. 27:299-307).

[0016] Although the mechanism for cholesterol transfer from the cell
surface is unknown, it is believed that the lipid-poor complex,
pre-beta-HDL, is the preferred acceptor for cholesterol transferred from
peripheral tissue involved in RCT. Cholesterol newly transferred to
pre-beta-1 HDL from the cell surface rapidly appears in the discoidal
pre-beta-2 HDL. PLTP may increase the rate of disc formation (Lagrost et
al., 1996, J. Biol. Chem. 271:19058-19065), but data indicating a role
for PLTP in RCT is lacking. LCAT reacts preferentially with discoidal and
spherical HDL, transferring the 2-acyl group of lecithin or
phosphatidylethanolamine to the free hydroxyl residue of fatty alcohols,
particularly cholesterol, to generate cholesteryl esters (retained in the
HDL) and lysolecithin. The LCAT reaction requires an apolipoprotein such
as apo A I or apo A-IV as an activator. ApoA-I is one of the natural
cofactors for LCAT. The conversion of cholesterol to its HDL-sequestered
ester prevents re-entry of cholesterol into the cell, resulting in the
ultimate removal of cellular cholesterol. Cholesteryl esters in the
mature HDL particles of the AI-HDL fraction are removed by the liver and
processed into bile more effectively than those derived from the
A/AII-HDL fraction. This may be due, in part, to the more effective
binding of AI-HDL to the hepatocyte membrane. Several HDL receptors have
been identified, the most well characterized of which is the scavenger
receptor class B, type I (SR BI) (Acton et al., 1996, Science
271:518-520). The SR-BI is expressed most abundantly in steroidogenic
tissues (e.g., the adrenals), and in the liver (Landshulz et al., 1996, J
Clin. Invest. 98:984-995; Rigotti et al., 1996, J. Biol. Chem.
271:33545-33549). Other proposed HDL receptors include HB1 and HB2
(Hidaka and Fidge, 1992, Biochem J. 15:161 7; Kurata et al., 1998, J.
Atherosclerosis and Thrombosis 4:112 7).

[0017] While there is a consensus that CETP is involved in the metabolism
of VLDL- and LDL-derived lipids, its role in RCT remains controversial.
However, changes in CETP activity or its acceptors, VLDL and LDL, play a
role in "remodeling" the HDL population. For example, in the absence of
CETP, the HDL becomes enlarged particles that are poorly removed from the
circulation (for reviews on RCT and HDL, See Fielding & Fielding, 1995,
J. Lipid Res. 36:211-228; Barrans et al., 1996, Biochem. Biophys. Acta.
1300:73-85; Hirano et al., 1997, Arterioscler. Thromb. Vasc. Biol.
17:1053-1059).

2.3 Reverse Transport of Other Lipids

[0018] HDL is not only involved in the reverse transport of cholesterol,
but also plays a role in the reverse transport of other lipids, i.e., the
transport of lipids from cells, organs, and tissues to the liver for
catabolism and excretion. Such lipids include sphingomyelin, oxidized
lipids, and lysophophatidylcholine. For example, Robins and Fasulo (1997,
J Clin. Invest. 99:380 384) have shown that HDL stimulates the transport
of plant sterol by the liver into bile secretions.

2.4 Peroxisome Proliferator Activated Receptor Pathway

[0019] Peroxisome proliferators are a structurally diverse group of
compounds that, when administered to rodents, elicit dramatic increases
in the size and number of hepatic and renal peroxisomes, as well as
concomitant increases in the capacity of peroxisomes to metabolize fatty
acids via increased expression of the enzymes required for the
f-oxidation cycle (Lazarow and Fujiki, 1985, Ann. Rev. Cell Biol. 1:489
530; Vamecq and Draye, 1989, Essays Biochem. 24:1115 225; and Nelali et
al., 1988, Cancer Res. 48:5316 5324). Chemicals included in this group
are the fibrate class ofhypolipidemic drugs, herbicides, and phthalate
plasticizers (Reddy and Lalwani, 1983, Crit. Rev. Toxicol. 12:1 58).
Peroxisome proliferation can also be elicited by dietary or physiological
factors, such as a high fat diet and cold acclimatization.

[0021] PPARs have been identified in the enhancers of a number of
gene-encoding proteins that regulate lipid metabolism. These proteins
include the three enzymes required for peroxisomal β-oxidation of
fatty acids; apolipoprotein A-I; medium chain acyl-CoA dehydrogenase, a
key enzyme in mitochondrial-oxidation; and aP2, a lipid binding protein
expressed exclusively in adipocytes (reviewed in Keller and Whali, 1993,
TEM, 4:291 296; see also Staels and Auwerx, 1998, Atherosclerosis 137
Suppl:S19 23). The nature of the PPAR target genes coupled with the
activation of PPARs by fatty acids and hypolipidemic drugs suggests a
physiological role for the PPARs in lipid homeostasis.

[0022] Pioglitazone, an antidiabetic compound of the thiazolidinedione
class, was reported to stimulate expression of a chimeric gene containing
the enhancer/promoter of the lipid binding protein aP2 upstream of the
chloroamphenicol acetyl transferase reporter gene (Harris and Kletzien,
1994, Mol. Pharmacol. 45:439 445). Deletion analysis led to the
identification of an approximately 30 bp region accounting for
pioglitazone responsiveness. In an independent study, this 30 bp fragment
was shown to contain a PPRE (Tontonoz et al., 1994, Nucleic Acids Res.
22:5628 5634). Taken together, these studies suggested the possibility
that the thiazolidinediones modulate gene expression at the
transcriptional level through interactions with a PPAR and reinforce the
concept of the interrelatedness of glucose and lipid metabolism.

2.5 Current Cholesterol Management Therapies

[0023] In the past two decades or so, the segregation of cholesterolemic
compounds into HDL and LDL regulators and recognition of the desirability
of decreasing blood levels of the latter has led to the development of a
number of drugs. However, many of these drugs have undesirable side
effects and/or are contraindicated in certain patients, particularly when
administered in combination with other drugs.

[0024] Bile-acid-binding resins are a class of drugs that interrupt the
recycling of bile acids from the intestine to the liver. Examples of
bile-acid-binding resins are cholestyramine (QUESTRAN LIGHT,
Bristol-Myers Squibb), and colestipol hydrochloride (COLESTID, Pharmacia
& Upjohn Company). When taken orally, these positively charged resins
bind to negatively charged bile acids in the intestine. Because the
resins cannot be absorbed from the intestine, they are excreted, carrying
the bile acids with them. The use of such resins, however, at best only
lowers serum cholesterol levels by about 20%. Moreover, their use is
associated with gastrointestinal side-effects, including constipation and
certain vitamin deficiencies. Moreover, since the resins bind to drugs,
other oral medications must be taken at least one hour before or four to
six hours subsequent to ingestion of the resin, complicating heart
patients' drug regimens.

[0025] The statins are inhibitors of cholesterol synthesis. Sometimes, the
statins are used in combination therapy with bile-acid-binding resins.
Lovastatin (MEVACOR, Merck & Co., Inc.), a natural product derived from a
strain of Aspergillus; pravastatin (PRAVACHOL, Bristol-Myers Squibb Co.);
and atorvastatin (LIPITOR, Warner Lambert) block cholesterol synthesis by
inhibiting HMGCoA reductase, the key enzyme involved in the cholesterol
biosynthetic pathway. Lovastatin significantly reduces serum cholesterol
and LDL-serum levels. However, serum HDL levels are only slightly
increased following lovastatin administration. The mechanism of the
LDL-lowering effect may involve both reduction of VLDL concentration and
induction of cellular expression of LDL-receptor, leading to reduced
production and/or increased catabolism of LDL. Side effects, including
liver and kidney dysfunction are associated with the use of these drugs.

[0026] Nicotinic acid, also known as niacin, is a water-soluble vitamin
B-complex used as a dietary supplement and antihyperlipidemic agent.
Niacin diminishes the production of VLDL and is effective at lowering
LDL. It is used in combination with bile-acid-binding resins. Niacin can
increase HDL when administered at therapeutically effective doses;
however, its usefulness is limited by serious side effects.

[0027] Fibrates are a class of lipid-lowering drugs used to treat various
forms of hyperlipidemia, elevated serum triglycerides, which may also be
associated with hypercholesterolemia. Fibrates appear to reduce the VLDL
fraction and modestly increase HDL; however, the effects of these drugs
on serum cholesterol is variable. In the United States, fibrates have
been approved for use as antilipidemic drugs, but have not received
approval as hypercholesterolemia agents. For example, clofibrate
(ATROMID-S, Wyeth-Ayerst Laboratories) is an antilipidemic agent that
acts to lower serum triglycerides by reducing the VLDL fraction. Although
ATROMID-S may reduce serum cholesterol levels in certain patient
subpopulations, the biochemical response to the drug is variable, and is
not always possible to predict which patients will obtain favorable
results. ATROMID-S has not been shown to be effective for prevention of
coronary heart disease. The chemically and pharmacologically related
drug, gemfibrozil (LOPID, Parke-Davis), is a lipid regulating agent which
moderately decreases serum triglycerides and VLDL cholesterol. LOPID also
increases HDL cholesterol, particularly the HDL2 and HDL3 subfractions,
as well as both the AI/AII-HDL fractions. However, the lipid response to
LOPID is heterogeneous, especially among different patient populations.
Moreover, while prevention of coronary heart disease was observed in male
patients between the ages of 40 and 55 without history or symptoms of
existing coronary heart disease, it is not clear to what extent these
findings can be extrapolated to other patient populations (e.g., women,
older and younger males). Indeed, no efficacy was observed in patients
with established coronary heart disease. Serious side-effects are
associated with the use of fibrates, including toxicity; malignancy,
particularly malignancy of gastrointestinal cancer; gallbladder disease;
and an increased incidence in non-coronary mortality. These drugs are not
indicated for the treatment of patients with high LDL or low HDL as their
only lipid abnormality.

[0028] Oral estrogen replacement therapy may be considered for moderate
hypercholesterolemia in post-menopausal women. However, increases in HDL
may be accompanied with an increase in triglycerides. Estrogen treatment
is, of course, limited to a specific patient population, postmenopausal
women, and is associated with serious side effects, including induction
of malignant neoplasms; gall bladder disease; thromboembolic disease;
hepatic adenoma; elevated blood pressure; glucose intolerance; and
hypercalcemia.

[0029] Long chain carboxylic acids, particularly long chain
α,ω-dicarboxylic acids with distinctive substitution
patterns, and their simple derivatives and salts, have been disclosed for
treating atherosclerosis, obesity, and diabetes (See, e.g., Bisgaier et
al., 1998, J Lipid Res. 39:17-30, and references cited therein;
International Patent Publication WO 98/30530; U.S. Pat. No. 4,689,344;
International Patent Publication WO 99/00116; and U.S. Pat. No.
5,756,344). However, some of these compounds, for example the
α,ω-dicarboxylic acids substituted at their
α,α'-carbons (U.S. Pat. No. 3,773,946), while having serum
triglyceride and serum cholesterol-lowering activities, have no value for
treatment of obesity and hypercholesterolemia (U.S. Pat. No. 4,689,344).

[0030] U.S. Pat. No. 4,689,344 discloses
β,β,β',β'-tetrasubstituted-α,ω-alkanedioi-
c acids that are optionally substituted at their
α,α,α',α'-positions, and alleges that they are
useful for treating obesity, hyperlipidemia, and diabetes. According to
this reference, both triglycerides and cholesterol are lowered
significantly by compounds such as
3,3,14,14-tetramethylhexadecane-1,16-dioic acid. U.S. Pat. No. 4,689,344
further discloses that the
β,β,β',β'-tetramethyl-alkanediols of U.S. Pat. No.
3,930,024 also are not useful for treating hypercholesterolemia or
obesity.

[0031] Other compounds are disclosed in U.S. Pat. No. 4,711,896. In U.S.
Pat. No. 5,756,544, α,ω-dicarboxylic acid-terminated dialkane
ethers are disclosed to have activity in lowering certain plasma lipids,
including Lp(a), triglycerides, VLDL-cholesterol, and LDL-cholesterol, in
animals, and elevating others, such as HDL-cholesterol. The compounds are
also stated to increase insulin sensitivity. In U.S. Pat. No. 4,613,593,
phosphates of dolichol, a polyprenol isolated from swine liver, are
stated to be useful in regenerating liver tissue, and in treating
hyperuricuria, hyperlipemia, diabetes, and hepatic diseases in general.

[0032] U.S. Pat. No. 4,287,200 discloses azolidinedione derivatives with
anti-diabetic, hypolipidemic, and anti-hypertensive properties. However,
the administration of these compounds to patients can produce side
effects such as bone marrow depression, and both liver and cardiac
cytotoxicity. Further, the compounds disclosed by U.S. Pat. No. 4,287,200
stimulate weight gain in obese patients.

[0033] It is clear that none of the commercially available cholesterol
management drugs has a general utility in regulating lipid, lipoprotein,
insulin and glucose levels in the blood. Thus, compounds that have one or
more of these utilities are clearly needed. Further, there is a clear
need to develop safer drugs that are efficacious at lowering serum
cholesterol, increasing HDL serum levels, preventing coronary heart
disease, and/or treating existing disease such as atherosclerosis,
obesity, diabetes, and other diseases that are affected by lipid
metabolism and/or lipid levels. There is also a clear need to develop
drugs that may be used with other lipid-altering treatment regimens in a
synergistic manner. There is still a further need to provide useful
therapeutic agents whose solubility and Hydrophile/Lipophile Balance
(HLB) can be readily varied.

[0034] Citation or identification of any reference in Section 2 of this
application is not an admission that such reference is available as prior
art to the present invention.

[0036] The invention further encompasses pharmaceutical compositions
comprising one or more compounds of the invention and a pharmaceutically
acceptable vehicle, excipient, or diluent. A pharmaceutically acceptable
vehicle can comprise a carrier, excipient, diluent, or a mixture thereof.

[0038] The invention also encompasses a method for inhibiting hepatic
fatty acid and sterol synthesis comprising administering to a patient in
need thereof a therapeutically effective amount of a compound of the
invention or a pharmaceutical composition comprising a compound of the
invention and a pharmaceutically acceptable vehicle, excipient, or
diluent.

[0039] The invention also encompasses a method of treating or preventing a
disease or disorder that is capable of being treated or prevented by
increasing HDL levels, which comprises administering to a patient in need
of such treatment or prevention a therapeutically effective amount of a
compound of the invention and a pharmaceutically acceptable vehicle,
excipient, or diluent.

[0040] The invention also encompasses a method of treating or preventing a
disease or disorder that is capable of being treated or prevented by
lowering LDL levels, which comprises administering to such patient in
need of such treatment or prevention a therapeutically effective amount
of a compound of the invention and a pharmaceutically acceptable vehicle,
excipient, or diluent.

[0041] The compounds of the invention favorably alter lipid metabolism in
animal models of dyslipidemia at least in part by enhancing oxidation of
fatty acids through the ACC/malonyl-CoA/CPT-I regulatory axis and
therefore the invention also encompasses methods of treatment or
prevention of metabolic syndrome disorders.

[0042] The invention further encompasses a method for reducing the fat
content of meat in livestock comprising administering to livestock in
need of such fat-content reduction a therapeutically effective amount of
a compound of the invention or a pharmaceutical composition comprising a
compound of the invention and a pharmaceutically acceptable vehicle,
excipient, or diluent.

[0043] The invention encompasses a method for reducing the cholesterol
content of a fowl egg comprising administering to a fowl species a
therapeutically effective amount of a compound of the invention or a
pharmaceutical composition comprising a compound of the invention and a
pharmaceutically acceptable vehicle, excipient, or diluent.

[0044] The present invention may be understood more fully by reference to
the detailed description and examples, which are intended to exemplify
non-limiting embodiments of the invention.

4. DEFINITIONS AND ABBREVIATIONS

[0045] Apo(a): apolipoprotein(a)

[0046] Apo A-I: apolipoprotein A-I

[0047] Apo B: apolipoprotein B

[0048] Apo E: apolipoprotein E

[0049] FH: Familial hypercholesterolemia

[0050] FCH: Familial combined hyperlipidemia

[0051] GDM: Gestational diabetes mellitus

[0052] HDL: High density lipoprotein

[0053] IDL: Intermediate density lipoprotein

[0054] IDDM: Insulin dependent diabetes mellitus

[0055] LDH: Lactate dehdyrogenase

[0056] LDL: Low density lipoprotein

[0057] Lp(a): Lipoprotein (a)

[0058] MODY: Maturity onset diabetes of the young

[0059] NIDDM: Non-insulin dependent diabetes mellitus

[0060] PPAR: Peroxisome proliferator activated receptor

[0061] RXR: Retinoid X receptor

[0062] VLDL: Very low density lipoprotein

[0063] As used herein, the phrase "compounds of the invention" means
compounds disclosed herein. Particular compounds of the invention are
compounds of formulas I, II, III, IV, and V, and pharmaceutically
acceptable salts, hydrates, enantiomers, diastereomer, racemates or
mixtures of stereoisomers thereof. The compounds of the invention are
identified herein by their chemical structure and/or chemical name. Where
a compound is referred to by both a chemical structure and a chemical
name, and the chemical structure and chemical name conflict, the chemical
structure is to be accorded more weight.

[0064] The compounds of the invention can contain one or more chiral
centers and/or double bonds and, therefore, exist as stereoisomers, such
as double-bond isomers (i.e., geometric isomers), enantiomers, or
diastereomers. According to the invention, the chemical structures
depicted herein, and therefore the compounds of the invention, encompass
all of the corresponding compounds' enantiomers and stereoisomers, that
is, both the stereomerically pure form (e.g., geometrically pure,
enantiomerically pure, or diastereomerically pure) and enantiomeric and
stereoisomeric mixtures.

[0065] As used herein, a composition that "substantially" comprises a
compound means that the composition contains more than about 80% by
weight, more preferably more than about 90% by weight, even more
preferably more than about 95% by weight, and most preferably more than
about 97% by weight of the compound.

[0066] As used herein, a reaction that is "substantially complete" means
that the reaction contains more than about 80% by weight of the desired
product, more preferably more than about 90% by weight of the desired
product, even more preferably more than about 95% by weight of the
desired product, and most preferably more than about 97% by weight of the
desired product.

[0067] A compound of the invention is considered optically active or
enantiomerically pure (i.e., substantially the R-form or substantially
the S-form) with respect to a chiral center when the compound is about
90% ee (enantiomeric excess) or greater, preferably, equal to or greater
than 95% ee with respect to a particular chiral center. A compound of the
invention is considered to be in enantiomerically-enriched form when the
compound has an enantiomeric excess of greater than about 1% ee,
preferably greater than about 5% ee, more preferably, greater than about
10% ee with respect to a particular chiral center. A compound of the
invention is considered diastereomerically pure with respect to multiple
chiral centers when the compound is about 90% de (diastereomeric excess)
or greater, preferably, equal to or greater than 95% de with respect to a
particular chiral center. A compound of the invention is considered to be
in diastereomerically-enriched form when the compound has an
diastereomeric excess of greater than about 1% de, preferably greater
than about 5% de, more preferably, greater than about 10% de with respect
to a particular chiral center. As used herein, a racemic mixture means
about 50% of one enantiomer and about 50% of is corresponding enantiomer
relative to all chiral centers in the molecule. Thus, the invention
encompasses all enantiomerically-pure, enantiomerically-enriched,
diastereomerically pure, diastereomerically enriched, and racemic
mixtures of compounds of Formulas I through V.

[0068] Enantiomeric and diastereomeric mixtures can be resolved into their
component enantiomers or stereoisomers by well known methods, such as
chiral-phase gas chromatography, chiral-phase high performance liquid
chromatography, crystallizing the compound as a chiral salt complex, or
crystallizing the compound in a chiral solvent. Enantiomers and
diastereomers can also be obtained from diastereomerically- or
enantiomerically-pure intermediates, reagents, and catalysts by well
known asymmetric synthetic methods.

[0069] The compounds of the invention are defined herein by their chemical
structures and/or chemical names. Where a compound is referred to by both
a chemical structure and a chemical name, and the chemical structure and
chemical name conflict, the chemical structure is determinative of the
compound's identity.

[0070] When administered to a patient, e.g., to an animal for veterinary
use or for improvement of livestock, or to a human for clinical use, the
compounds of the invention are administered in isolated form or as the
isolated form in a pharmaceutical composition. As used herein, "isolated"
means that the compounds of the invention are separated from other
components of either (a) a natural source, such as a plant or cell,
preferably bacterial culture, or (b) a synthetic organic chemical
reaction mixture. Preferably, via conventional techniques, the compounds
of the invention are purified. As used herein, "purified" means that when
isolated, the isolate contains at least 95%, preferably at least 98%, of
a single hydroxy compound of the invention by weight of the isolate.

[0071] The phrase "pharmaceutically acceptable salt(s)," as used herein
includes, but is not limited to, salts of acidic or basic groups that may
be present in the compounds of the invention. Compounds that are basic in
nature are capable of forming a wide variety of salts with various
inorganic and organic acids. The acids that may be used to prepare
pharmaceutically acceptable acid addition salts of such basic compounds
are those that form non-toxic acid addition salts, i.e., salts containing
pharmacologically acceptable anions, including but not limited to
sulfuric, citric, maleic, acetic, oxalic, hydrochloride, hydrobromide,
hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate,
isonicotinate, acetate, lactate, salicylate, citrate, acid citrate,
tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate,
succinate, maleate, gentisinate, fumarate, gluconate, glucaronate,
saccharate, formate, benzoate, glutamate, methanesulfonate,
ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e.,
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds of the
invention that include an amino moiety also can form pharmaceutically
acceptable salts with various amino acids, in addition to the acids
mentioned above. Compounds of the invention that are acidic in nature are
capable of forming base salts with various pharmacologically acceptable
cations. Examples of such salts include alkali metal or alkaline earth
metal salts and, particularly, calcium, magnesium, sodium lithium, zinc,
potassium, and iron salts.

[0072] As used herein, the term "hydrate" means a compound of the
invention or a salt thereof, that further includes a stoichiometric or
non-stoichiometric amount of water bound by non-covalent intermolecular
forces. The term hydrate includes solvates, which are stoichiometric or
non-stoichiometric amounts of a solvent bound by non-covalent
intermolecular forces. Preferred solvents are volatile, non-toxic, and/or
acceptable for administration to humans in trace amounts.

[0074] As used herein, the term "altering glucose metabolism" indicates an
observable (measurable) change in at least one aspect of glucose
metabolism, including but not limited to total blood glucose content,
blood insulin, the blood insulin to blood glucose ratio, insulin
sensitivity, and oxygen consumption.

[0076] As used herein, the term an "alkenyl group" means a monovalent
unbranched or branched hydrocarbon chain having one or more double bonds
therein. The double bond of an alkenyl group can be unconjugated or
conjugated to another unsaturated group. Suitable alkenyl groups include,
but are not limited to (C2-C6)alkenyl groups, such as vinyl,
allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl,
2-ethylhexenyl, 2-propyl-2-butenyl, 4-(2-methyl-3-butene)-pentenyl. An
alkenyl group can be unsubstituted or substituted with one or two
suitable substituents.

[0077] As used herein, the term an "alkynyl group" means monovalent
unbranched or branched hydrocarbon chain having one or more triple bonds
therein. The triple bond of an alkynyl group can be unconjugated or
conjugated to another unsaturated group. Suitable alkynyl groups include,
but are not limited to, (C2-C6)alkynyl groups, such as ethynyl,
propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl-1-butynyl,
4-propyl-2-pentynyl, and 4-butyl-2-hexynyl. An alkynyl group can be
unsubstituted or substituted with one or two suitable substituents.

[0078] As used herein, the term an "aryl group" means a monocyclic or
polycyclic-aromatic radical comprising carbon and hydrogen atoms.
Examples of suitable aryl groups include, but are not limited to, phenyl,
tolyl, anthacenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as
benzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl. An
aryl group can be unsubstituted or substituted with one or two suitable
substituents. Preferably, the aryl group is a monocyclic ring, wherein
the ring comprises 6 carbon atoms, referred to herein as "(C6)aryl".

[0079] As used herein, the term an "heteroaryl group" means a monocyclic-
or polycyclic aromatic ring comprising carbon atoms, hydrogen atoms, and
one or more heteroatoms, preferably 1 to 3 heteroatoms, independently
selected from nitrogen, oxygen, and sulfur. Illustrative examples of
heteroaryl groups include, but are not limited to, pyridinyl,
pyridazinyl, pyrimidinyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl,
imidazolyl, (1,2,3)- and (1,2,4)-triazolyl, pyrazinyl, pyrimidinyl,
tetrazolyl, furyl, thiophenyl, isoxazolyl, thiazolyl, furyl, phenyl,
isoxazolyl, and oxazolyl. A heteroaryl group can be unsubstituted or
substituted with one or two suitable substituents. Preferably, a
heteroaryl group is a monocyclic ring, wherein the ring comprises 2 to 5
carbon atoms and 1 to 3 heteroatoms, referred to herein as
"(C2-C5)heteroaryl".

[0080] As used herein, the term "cycloalkyl group" means a monocyclic or
polycyclic saturated ring comprising carbon and hydrogen atoms and having
no carbon-carbon multiple bonds. Examples of cycloalkyl groups include,
but are not limited to, (C3-C7)cycloalkyl groups, such as
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, and
saturated cyclic and bicyclic terpenes. A cycloalkyl group can be
unsubstituted or substituted by one or two suitable substituents.
Preferably, the cycloalkyl group is a monocyclic ring or bicyclic ring.

[0081] As used herein, the term "heterocycloalkyl group" means a
monocyclic or polycyclic ring comprising carbon and hydrogen atoms and at
least one heteroatom, preferably, 1 to 3 heteroatoms selected from
nitrogen, oxygen, and sulfur, and having no unsaturation. Examples of
heterocycloalkyl groups include pyrrolidinyl, pyrrolidino, piperidinyl,
piperidino, piperazinyl, piperazino, morpholinyl, morpholino,
thiomorpholinyl, thiomorpholino, and pyranyl. A heterocycloalkyl group
can be unsubstituted or substituted with one or two suitable
substituents. Preferably, the heterocycloalkyl group is a monocyclic or
bicyclic ring, more preferably, a monocyclic ring, wherein the ring
comprises from 3 to 6 carbon atoms and form 1 to 3 heteroatoms, referred
to herein as (C1-C6)heterocycloalkyl.

[0082] As used herein, the terms "heterocyclic radical" or "heterocyclic
ring" mean a heterocycloalkyl group or a heteroaryl group.

[0083] As used herein, the term "alkoxy group" means an --O-alkyl group,
wherein alkyl is as defined above. An alkoxy group can be unsubstituted
or substituted with one or two suitable substituents. Preferably, the
alkyl chain of an alkyloxy group is from 1 to 6 carbon atoms in length,
referred to herein as "(C1-C6)alkoxy".

[0084] As used herein, the term "aryloxy group" means an --O-aryl group,
wherein aryl is as defined above. An aryloxy group can be unsubstituted
or substituted with one or two suitable substituents. Preferably, the
aryl ring of an aryloxy group is a monocyclic ring, wherein the ring
comprises 6 carbon atoms, referred to herein as "(C6)aryloxy".

[0085] As used herein, the term "benzyl" means --CH2-phenyl.

[0086] As used herein, the term "phenyl" means --C6H5. A phenyl
group can be unsubstituted or substituted with one or two suitable
substituents, wherein the substituent replaces an H of the phenyl group.
As used herein, "Ph," represents a phenyl group or a substituted phenyl
group.

[0087] As used herein, the term "hydrocarbyl" group means a monovalent
group selected from (C1-C5)alkyl, (C2-C5)alkenyl, and
(C2-C5)alkynyl, optionally substituted with one or two suitable
substituents. Preferably, the hydrocarbon chain of a hydrocarbyl group is
from 1 to 6 carbon atoms in length, referred to herein as
"(C1-C6)hydrocarbyl".

[0088] As used herein, a "carbonyl" group is a divalent group of the
formula C(O).

[0089] As used herein, the term "alkoxycarbonyl" group means a monovalent
group of the formula --C(O)-alkoxy. Preferably, the hydrocarbon chain of
an alkoxycarbonyl group is from 1 to 8 carbon atoms in length, referred
to herein as a "lower alkoxycarbonyl" group.

[0090] As used herein, a "carbamoyl" group means the radical
--C(O)N(R')2, wherein R' is chosen from the group consisting of
hydrogen, alkyl, and aryl.

[0091] As used herein, "halogen" means fluorine, chlorine, bromine, or
iodine. Accordingly, the meaning of the terms "halo" and "Hal" encompass
fluoro, chloro, bromo, and iodo.

[0092] As used herein, a "suitable substituent" means a group that does
not nullify the synthetic or pharmaceutical utility of the compounds of
the invention or the intermediates useful for preparing them. Examples of
suitable substituents include, but are not limited to:
(C1-C8)alkyl; (C1-C5)alkenyl;
(C1-C5)alkynyl; (C6)aryl; (C2-C5)heteroaryl;
(C3-C7)cycloalkyl; (C1-C8)alkoxy; (C6)aryloxy;
--CN; --OH; oxo; halo, --CO2H; --NH2;
--NH((C1-C8)alkyl); --N((C1-C5)alkyl)2;
--NH((C6)aryl); --N((C6)aryl)2; --CHO;
--CO((C1-C8)alkyl); --CO((C6)aryl);
--CO2((C1-C8)alkyl); and --CO2((C6)aryl). One of
skill in the art can readily choose a suitable substituent based on the
stability and pharmacological and synthetic activity of the compound of
the invention.

[0093] As used herein, a composition that is "substantially free" of a
compound means that the composition contains less than about 20% by
weight, more preferably less than about 10% by weight, even more
preferably less than about 5% by weight, and most preferably less than
about 3% by weight of the compound.

5. DETAILED DESCRIPTION OF THE INVENTION

[0094] The compounds of the invention are useful in medical applications
for treating or preventing a variety of diseases and disorders such as,
but not limited to, cardiovascular disease, stroke, and peripheral
vascular disease; dyslipidemia; dyslipoproteinemia; a disorder of glucose
metabolism; Alzheimer's Disease; Parkinson's Disease, diabetic
nephropathy, diabetic retinopathy, insulin resistance, Syndrome X; a
peroxisome proliferator activated receptor-associated disorder;
septicemia; a thrombotic disorder; obesity; pancreatitis; hypertension;
renal disease; cancer; inflammation; inflammatory muscle diseases, such
as polymylagia rheumatica, polymyositis, and fibrositis; impotence;
gastrointestinal disease; irritable bowel syndrome; inflammatory bowel
disease; inflammatory disorders, such as asthma, vasculitis, ulcerative
colitis, Crohn's disease, Kawasaki disease, Wegener's granulomatosis,
(RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), and
autoimmune chronic hepatitis; arthritis, such as rheumatoid arthritis,
juvenile rheumatoid arthritis, and osteoarthritis; osteoporosis, soft
tissue rheumatism, such as tendonitis; bursitis; autoimmune disease, such
as systemic lupus and erythematosus; scleroderma; ankylosing spondylitis;
gout; pseudogout; non-insulin dependent diabetes mellitus; polycystic
ovarian disease; hyperlipidemias, such as familial hypercholesterolemia
(FH), familial combined hyperlipidemia (FCH); lipoprotein lipase
deficiencies, such as hypertriglyceridemia, hypoalphalipoproteinemia, and
hypercholesterolemia; lipoprotein abnormalities associated with diabetes;
lipoprotein abnormalities associated with obesity; and lipoprotein
abnormalities associated with Alzheimer's Disease. The compounds and
compositions of the invention are useful for treatment or prevention of
high levels of blood triglycerides, high levels of low density
lipoprotein cholesterol, high levels of apolipoprotein B, high levels of
lipoprotein Lp(a) cholesterol, high levels of very low density
lipoprotein cholesterol, high levels of fibrinogen, high levels of
insulin, high levels of glucose, and low levels of high density
lipoprotein cholesterol. The compounds and compositions of the invention
also have utility for treatment of NIDDM without increasing weight gain.
The compounds of the invention may also be used to reduce the fat content
of meat in livestock and reduce the cholesterol content of eggs.

or a pharmaceutically acceptable salt, hydrate, solvate or a mixture
thereof, wherein:

[0097] (a) each occurrence of m is independently an
integer ranging from 0 to 5;

[0098] (b) each occurrence of n is
independently an integer ranging from 3 to 7;

[0099] (c) X is
(CH2)z or Ph, wherein z is an integer from 0 to 4;

[0100] (d)
each occurrence of R1 and R2 is independently
(C1-C6)alkyl, (C2-C6)alkenyl,
(C2-C6)alkynyl, phenyl, benzyl, or R1 and R2 and the
carbon to which they are both attached are taken together to form a
(C3-C7)cycloakyl group;

[0101] (e) each occurrence of R11
and R12 and the carbon to which they are both attached are taken
together to form a (C3-C7)cycloakyl group;

[0118] (a) each occurrence of R1 and R2 is
independently (C1-C6)alkyl, (C2-C6)alkenyl,
(C2-C6)alkynyl, phenyl, benzyl, or R1 and R2 and the
carbon to which they are both attached are taken together to form a
(C3-C7)cycloakyl group;

[0119] (b) each occurrence of R11
and R12 and the carbon to which they are both attached are taken
together to form a (C3-C7)cycloakyl group;

[0120] (c) each
occurrence of n is independently an integer ranging from 1 to 7;

[0121]
(d) X is (CH2)z or Ph, wherein z is an integer from 0 to 4;

[0122] (e) each occurrence of m is independently an integer ranging from
0 to 4;

[0131] (a) each occurrence of R and R2 is
independently (C1-C6)alkyl, (C2-C6)alkenyl,
(C2-C6)alkynyl, phenyl, benzyl, or R1 and R2 and the
carbon to which they are both attached are taken together to form a
(C3-C7)cycloakyl group;

[0132] (b) each occurrence of R11
and R12 and the carbon to which they are both attached are taken
together to form a (C3-C7)cycloakyl group;

[0133] (c) each
occurrence of n is independently an integer ranging from 1 to 7;

[0134]
(d) X is (CH2)z or Ph, wherein z is an integer from 0 to 4;

[0135] (e) each occurrence of m is independently an integer ranging from
0 to 4;

[0143] (a) each occurrence of R1 and R2 is
independently (C1-C6)alkyl, (C2-C6)alkenyl,
(C2-C6)alkynyl, phenyl, benzyl, or R1 and R2 and the
carbon to which they are both attached are taken together to form a
(C3-C7)cycloakyl group;

[0144] (b) each occurrence of R11
and R12 and the carbon to which they are both attached are taken
together to form a (C3-C7)cycloakyl group;

[0145] (c) each
occurrence of n is independently an integer ranging from 1 to 7;

[0146]
(d) X is (CH2)z or Ph, wherein z is an integer from 0 to 4;

[0147] (e) each occurrence of m is independently an integer ranging from
0 to 4;

[0155] (a) each occurrence of R1 and R2 is
independently (C1-C6)alkyl, (C2-C6)alkenyl,
(C2-C6)alkynyl, phenyl, benzyl, or R1 and R2 and the
carbon to which they are both attached are taken together to form a
(C3-C7)cycloakyl group;

[0156] (b) each occurrence of R11
and R12 and the carbon to which they are both attached are taken
together to form a (C3-C7)cycloakyl group;

[0157] (c) each
occurrence of n is independently an integer ranging from 1 to 7;

[0158]
(d) X is (CH2)z or Ph, wherein z is an integer from 0 to 4;

[0159] (e) each occurrence of m is independently an integer ranging from
0 to 4; and

[0162] (i) R3 is (C1-C5)alkyl,
(C2-C6)alkenyl, (C1-C6)alkynyl, phenyl, or benzyl and
is unsubstituted or substituted with one or more halo, OH,
(C1-C6)alkoxy, or phenyl groups,

[0163] (ii) each occurrence of
R4 is independently H, (C1-C5)alkyl,
(C2-C6)alkenyl, or (C2-C6)alkynyl and is
unsubstituted or substituted with one or two halo, OH, C1-C6
alkoxy, or phenyl groups; and

[0164] (iii) each occurrence of R5 is
independently H, (C1-C5)alkyl, (C2-C6)alkenyl, or
(C2-C5)alkynyl.

[0165] The present invention further encompasses pharmaceutical
compositions comprising one or more compounds of the invention.
Particular pharmaceutical compositions further comprise pharmaceutically
acceptable vehicle, which can comprise a carrier, excipient, diluent, or
a mixture thereof.

[0167] The present invention further encompasses a method of treating or
preventing a disease or disorder that is capable of being treated or
prevented by increasing HDL levels, which comprises administering to a
patient in need of such treatment or prevention a therapeutically
effective amount of a compound.

[0168] The present invention further encompasses a method of treating or
preventing a disease or disorder that is capable of being treated or
prevented by decreasing LDL levels, which comprises administering to a
patient in need of such treatment or prevention a therapeutically
effective amount of a compound.

[0169] The present invention further encompasses a method for reducing the
fat content of meat in livestock comprising administering to livestock in
need of such fat-content reduction a therapeutically effective amount of
a compound of the invention or a pharmaceutical composition.

[0170] The present invention encompasses a method for reducing the
cholesterol content of a fowl egg comprising administering to a fowl
species a therapeutically effective amount of a compound of the
invention.

[0171] The compounds of the invention are particularly useful when
incorporated in a pharmaceutical composition comprising a carrier,
excipient, diluent, or a mixture thereof. However, a compound of the
invention need not be administered with excipients or diluents and can be
delivered in a gel cap or drug delivery device.

[0172] In certain embodiments of the invention, a compound of the
invention is administered in combination with another therapeutic agent.
The other therapeutic agent provides additive or synergistic value
relative to the administration of a compound of the invention alone.
Examples of other therapeutic agents include, but are not limited to, a
lovastatin; a thiazolidinedione or fibrate; a bile-acid-binding-resin; a
niacin; an anti-obesity drug; a hormone; a tyrophostine; a
sulfonylurea-based drug; a biguanide; an a-glucosidase inhibitor; an
apolipoprotein A-I agonist; apolipoprotein E; a cardiovascular drug; an
HDL-raising drug; an HDL enhancer; or a regulator of the apolipoprotein
A-I, apolipoprotein A-IV and/or apolipoprotein genes.

[0173] Illustrative examples of compounds of the invention include those
shown below, and pharmaceutically acceptable salts, hydrates,
enantiomers, diastereomers, and geometric isomers thereof:

[0174] The compounds of the invention can be obtained via the synthetic
methodology illustrated in Scheme 1. Starting materials useful for
preparing the compounds of the invention and intermediates thereof, are
commercially available or can be prepared form commercially available
materials using known synthetic methods and reagents.

[0175] Scheme 1 illustrates the synthesis of cycloalkyl-hydroxyl compounds
of the formula 2 and 4 wherein n is an integer in the range from 2-12 and
m is an integer in the range from 1-4.

[0179] In certain embodiments, the compounds of the invention or the
compositions of the invention are administered to a patient, preferably a
human, as a preventative measure against such diseases. As used herein,
"prevention" or "preventing" refers to a reduction of the risk of
acquiring a given disease or disorder. In a preferred mode of the
embodiment, the compositions of the present invention are administered as
a preventative measure to a patient, preferably a human having a genetic
predisposition to a aging, Alzheimer's Disease, cancer, cardiovascular
disease, diabetic nephropathy, diabetic retinopathy, a disorder of
glucose metabolism, dyslipidemia, dyslipoproteinemia, enhancing bile
production, enhancing reverse lipid transport, hypertension, impotence,
inflammation, insulin resistance, lipid elimination in bile, modulating C
reactive protein, obesity, oxysterol elimination in bile, pancreatitis,
Parkinson's disease, a peroxisome proliferator activated
receptor-associated disorder, phospholipid elimination in bile, renal
disease, septicemia, metabolic syndrome disorders (e.g., Syndrome X), a
thrombotic disorder, inflammatory processes and diseases like
gastrointestinal disease, irritable bowel syndrome (IBS), inflammatory
bowel disease (e.g., Crohn's Disease, ulcerative colitis), arthritis
(e.g., rheumatoid arthritis, osteoarthritis), autoimmune disease (e.g.,
systemic lupus erythematosus), scleroderma, ankylosing spondylitis, gout
and pseudogout, muscle pain: polymyositis/polymyalgia
rheumaticalfibrositis; infection and arthritis, juvenile rheumatoid
arthritis, tendonitis, bursitis and other soft tissue rheumatism.
Examples of such genetic predispositions include but are not limited to
the ε4 allele of apolipoprotein E, which increases the likelihood
of Alzheimer's Disease; a loss of function or null mutation in the
lipoprotein lipase gene coding region or promoter (e.g., mutations in the
coding regions resulting in the substitutions D9N and N291S; for a review
of genetic mutations in the lipoprotein lipase gene that increase the
risk of cardiovascular diseases, dyslipidemias and dyslipoproteinemias,
see Hayden and Ma, 1992, Mol. Cell Biochem. 113:171-176); and familial
combined hyperlipidemia and familial hypercholesterolemia.

[0180] In another preferred mode of the embodiment, the compounds of the
invention or compositions of the invention are administered as a
preventative measure to a patient having a non-genetic predisposition to
a aging, Alzheimer's Disease, cancer, cardiovascular disease, diabetic
nephropathy, diabetic retinopathy, a disorder of glucose metabolism,
dyslipidemia, dyslipoproteinemia, enhancing bile production, enhancing
reverse lipid transport, hypertension, impotence, inflammation, insulin
resistance, lipid elimination in bile, modulating C reactive protein,
obesity, oxysterol elimination in bile, pancreatitis, Parkinson's
disease, a peroxisome proliferator activated receptor-associated
disorder, phospholipid elimination in bile, renal disease, septicemia,
metabolic syndrome disorders (e.g., Syndrome X), a thrombotic disorder,
inflammatory processes and diseases like gastrointestinal disease,
irritable bowel syndrome (IBS), inflammatory bowel disease (e.g., Crohn's
Disease, ulcerative colitis), arthritis (e.g., rheumatoid arthritis,
osteoarthritis), autoimmune disease (e.g., systemic lupus erythematosus),
scleroderma, ankylosing spondylitis, gout and pseudogout, muscle pain:
polymyositis/polymyalgia rheumatica/fibrositis; infection and arthritis,
juvenile rheumatoid arthritis, tendonitis, bursitis and other soft tissue
rheumatism. Examples of such non-genetic predispositions include but are
not limited to cardiac bypass surgery and percutaneous transluminal
coronary angioplasty, which often lead to restenosis, an accelerated form
of atherosclerosis; diabetes in women, which often leads to polycystic
ovarian disease; and cardiovascular disease, which often leads to
impotence. Accordingly, the compositions of the invention may be used for
the prevention of one disease or disorder and concurrently treating
another (e.g., prevention of polycystic ovarian disease while treating
diabetes; prevention of impotence while treating a cardiovascular
disease).

5.2.1 Treatment of Cardiovascular Diseases

[0181] The present invention provides methods for the treatment or
prevention of a cardiovascular disease, comprising administering to a
patient a therapeutically effective amount of a compound or a composition
comprising a compound of the invention and a pharmaceutically acceptable
vehicle. As used herein, the term "cardiovascular diseases" refers to
diseases of the heart and circulatory system. These diseases are often
associated with dyslipoproteinemias and/or dyslipidemias. Cardiovascular
diseases which the compositions of the present invention are useful for
preventing or treating include but are not limited to arteriosclerosis;
atherosclerosis; stroke; ischemia; endothelium dysfunctions, in
particular those dysfunctions affecting blood vessel elasticity;
peripheral vascular disease; coronary heart disease; myocardial
infarcation; cerebral infarction and restenosis.

5.2.2 Treatment of Dyslipidemias

[0182] The present invention provides methods for the treatment or
prevention of a dyslipidemia comprising administering to a patient a
therapeutically effective amount of a compound or a composition
comprising a compound of the invention and a pharmaceutically acceptable
vehicle.

[0183] As used herein, the term "dyslipidemias" refers to disorders that
lead to or are manifested by aberrant levels of circulating lipids. To
the extent that levels of lipids in the blood are too high, the
compositions of the invention are administered to a patient to restore
normal levels. Normal levels of lipids are reported in medical treatises
known to those of skill in the art. For example, recommended blood levels
of LDL, HDL, free triglycerides and others parameters relating to lipid
metabolism can be found at the web site of the American Heart Association
and that of the National Cholesterol Education Program of the National
Heart, Lung and Blood Institute
(http://www.americanheart.org/cholesterol/about_level.html and
http://www.nhlbi.nih.gov/health/public/heartlchol/hbc_what.html,
respectively). At the present time, the recommended level of HDL
cholesterol in the blood is above 35 mg/dL; the recommended level of LDL
cholesterol in the blood is below 130 mg/dL; the recommended LDL:HDL
cholesterol ratio in the blood is below 5:1, ideally 3.5:1; and the
recommended level of free triglycerides in the blood is less than 200
mg/dL.

[0184] Dyslipidemias which the compositions of the present invention are
useful for preventing or treating include but are not limited to
hyperlipidemia and low blood levels of high density lipoprotein (HDL)
cholesterol. In certain embodiments, the hyperlipidemia for prevention or
treatment by the compounds of the present invention is familial
hypercholesterolemia; familial combined hyperlipidemia; reduced or
deficient lipoprotein lipase levels or activity, including reductions or
deficiencies resulting from lipoprotein lipase mutations;
hypertriglyceridemia; hypercholesterolemia; high blood levels of urea
bodies (e.g. β-OH butyric acid); high blood levels of Lp(a)
cholesterol; high blood levels of low density lipoprotein (LDL)
cholesterol; high blood levels of very low density lipoprotein (VLDL)
cholesterol and high blood levels ofnon-esterified fatty acids.

[0185] The present invention further provides methods for altering lipid
metabolism in a patient, e.g., reducing LDL in the blood of a patient,
reducing free triglycerides in the blood of a patient, increasing the
ratio of HDL to LDL in the blood of a patient, and inhibiting saponified
and/or non-saponified fatty acid synthesis, said methods comprising
administering to the patient a compound or a composition comprising a
compound of the invention in an amount effective alter lipid metabolism.

5.2.3 Treatment of Dyslipoproteinemias

[0186] The present invention provides methods for the treatment or
prevention of a dyslipoproteinemia comprising administering to a patient
a therapeutically effective amount of a compound or a composition
comprising a compound of the invention and a pharmaceutically acceptable
vehicle.

[0187] As used herein, the term "dyslipoproteinemias" refers to disorders
that lead to or are manifested by aberrant levels of circulating
lipoproteins. To the extent that levels of lipoproteins in the blood are
too high, the compositions of the invention are administered to a patient
to restore normal levels. Conversely, to the extent that levels of
lipoproteins in the blood are too low, the compositions of the invention
are administered to a patient to restore normal levels, Normal levels of
lipoproteins are reported in medical treatises known to those of skill in
the art.

[0188] Dyslipoproteinemias which the compositions of the present invention
are useful for preventing or treating include but are not limited to high
blood levels of LDL; high blood levels of apolipoprotein B (apo B); high
blood levels of Lp(a); high blood levels of apo(a); high blood levels of
VLDL; low blood levels of HDL; reduced or deficient lipoprotein lipase
levels or activity, including reductions or deficiencies resulting from
lipoprotein lipase mutations; hypoalphalipoproteinemia; lipoprotein
abnormalities associated with diabetes; lipoprotein abnormalities
associated with obesity; lipoprotein abnormalities associated with
Alzheimer's Disease; and familial combined hyperlipidemia.

[0189] The present invention further provides methods for reducing apo
C-II levels in the blood of a patient; reducing apo C-III levels in the
blood of a patient; elevating the levels of HDL associated proteins,
including but not limited to apo A-I, apo A-II, apo A-IV and apo E in the
blood of a patient; elevating the levels of apo E in the blood of a
patient, and promoting clearance of triglycerides from the blood of a
patient, said methods comprising administering to the patient a compound
or a composition comprising a compound of the invention in an amount
effective to bring about said reduction, elevation or promotion,
respectively.

5.2.4 Treatment of Glucose Metabolism Disorders

[0190] The present invention provides methods for the treatment or
prevention of a glucose metabolism disorder, comprising administering to
a patient a therapeutically effective amount of a compound or a
composition comprising a compound of the invention and a pharmaceutically
acceptable vehicle. As used herein, the term "glucose metabolism
disorders" refers to disorders that lead to or are manifested by aberrant
glucose storage and/or utilization. To the extent that indicia of glucose
metabolism (i.e., blood insulin, blood glucose) are too high, the
compositions of the invention are administered to a patient to restore
normal levels. Conversely, to the extent that indicia of glucose
metabolism are too low, the compositions of the invention are
administered to a patient to restore normal levels. Normal indicia of
glucose metabolism are reported in medical treatises known to those of
skill in the art.

[0191] Glucose metabolism disorders which the compositions of the present
invention are useful for preventing or treating include but are not
limited to impaired glucose tolerance; insulin resistance; insulin
resistance related breast, colon or prostate cancer; diabetes, including
but not limited to non-insulin dependent diabetes mellitus (NIDDM),
insulin dependent diabetes mellitus (IDDM), gestational diabetes mellitus
(GDM), and maturity onset diabetes of the young (MODY); pancreatitis;
hypertension; polycystic ovarian disease; and high levels of blood
insulin and/or glucose.

[0192] The present invention further provides methods for altering glucose
metabolism in a patient, for example to increase insulin sensitivity
and/or oxygen consumption of a patient, said methods comprising
administering to the patient a compound or a composition comprising a
compound of the invention in an amount effective to alter glucose
metabolism.

5.2.5 Treatment of PPAR-Associated Disorders

[0193] The present invention provides methods for the treatment or
prevention of a PPAR-associated disorder, comprising administering to a
patient a therapeutically effective amount of a compound or a composition
comprising a compound of the invention and a pharmaceutically acceptable
vehicle. As used herein, "treatment or prevention of PPAR associated
disorders" encompasses treatment or prevention of rheumatoid arthritis;
multiple sclerosis; psoriasis; inflammatory bowel diseases; breast; colon
or prostate cancer; low levels of blood HDL; low levels of blood, lymph
and/or cerebrospinal fluid apo E; low blood, lymph and/or cerebrospinal
fluid levels of apo A-I; high levels of blood VLDL; high levels of blood
LDL; high levels of blood triglyceride; high levels of blood apo B; high
levels of blood apo C-III and reduced ratio of post-heparin hepatic
lipase to lipoprotein lipase activity. HDL may be elevated in lymph
and/or cerebral fluid.

5.2.6 Treatment of Renal Diseases

[0194] The present invention provides methods for the treatment or
prevention of a renal disease, comprising administering to a patient a
therapeutically effective amount of a compound or a composition
comprising a compound of the invention and a pharmaceutically acceptable
vehicle. Renal diseases that can be treated by the compounds of the
present invention include glomerular diseases (including but not limited
to acute and chronic glomerulonephritis, rapidly progressive
glomerulonephritis, nephrotic syndrome, focal proliferative
glomerulonephritis, glomerular lesions associated with systemic disease,
such as systemic lupus erythematosus, Goodpasture's syndrome, multiple
myeloma, diabetes, neoplasia, sickle cell disease, and chronic
inflammatory diseases), tubular diseases (including but not limited to
acute tubular necrosis and acute renal failure, polycystic renal
diseasemedullary sponge kidney, medullary cystic disease, nephrogenic
diabetes, and renal tubular acidosis), tubulointerstitial diseases
(including but not limited to pyelonephritis, drug and toxin induced
tubulointerstitial nephritis, hypercalcemic nephropathy, and hypokalemic
nephropathy) acute and rapidly progressive renal failure, chronic renal
failure, nephrolithiasis, or tumors (including but not limited to renal
cell carcinoma and nephroblastoma). In a most preferred embodiment, renal
diseases that are treated by the compounds of the present invention are
vascular diseases, including but not limited to hypertension,
nephrosclerosis, microangiopathic hemolytic anemia, atheroembolic renal
disease, diffuse cortical necrosis, and renal infarcts.

5.2.7 Treatment of Cancer

[0195] The present invention provides methods for the treatment or
prevention of cancer, comprising administering to a patient a
therapeutically effective amount of a compound or a composition
comprising a compound of the invention and a pharmaceutically acceptable
vehicle. Types of cancer that can be treated using a Compound of the
Invention include, but are not limited to, those listed in Table 2.

[0196] Cancer, including, but not limited to, a tumor, metastasis, or any
disease or disorder characterized by uncontrolled cell growth, can be
treated or prevented by administration of a Compound of the Invention.

5.2.8 Treatment of Other Diseases

[0197] The present invention provides methods for the treatment or
prevention of Alzheimer's Disease, Syndrome X, septicemia, thrombotic
disorders, obesity, pancreatitis, hypertension, inflammation, and
impotence, comprising administering to a patient a therapeutically
effective amount of a compound or a composition comprising a compound of
the invention and a pharmaceutically acceptable vehicle.

[0198] As used herein, "treatment or prevention of Alzheimer's Disease"
encompasses treatment or prevention of lipoprotein abnormalities
associated with Alzheimer's Disease.

[0199] As used herein, "treatment or prevention of Syndrome X or Metabolic
Syndrome" encompasses treatment or prevention of a symptom thereof,
including but not limited to impaired glucose tolerance, hypertension and
dyslipidemia/dyslipoproteinemia.

[0200] As used herein, "treatment or prevention of septicemia" encompasses
treatment or prevention of septic shock.

[0201] As used herein, "treatment or prevention of thrombotic disorders"
encompasses treatment or prevention of high blood levels of fibrinogen
and promotion of fibrinolysis.

[0202] In addition to treating or preventing obesity, the compositions of
the invention can be administered to an individual to promote weight
reduction of the individual.

[0203] As used herein, "treatment or prevention of diabetic nephropathy"
encompasses treating or preventing kidney disease that develops as a
result of diabetes mellitus (DM). Diabetes mellitus is a disorder in
which the body is unable to metabolize carbohydrates (e.g., food
starches, sugars, cellulose) properly. The disease is characterized by
excessive amounts of sugar in the blood (hyperglycemia) and urine;
inadequate production and/or utilization of insulin; and by thirst,
hunger, and loss of weight. Thus, the compounds of the invention can also
be used to treat or prevent diabetes mellitus.

[0204] As used herein, "treatment or prevention of diabetic retinopathy"
encompasses treating or preventing complications of diabetes that lead to
or cause blindness. Diabetic retinopathy occurs when diabetes damages the
tiny blood vessels inside the retina, the light-sensitive tissue at the
back of the eye.

[0205] As used herein, "treatment or prevention of impotence" includes
treating or preventing erectile dysfunction, which encompasses the
repeated inability to get or keep an erection firm enough for sexual
intercourse. The word "impotence" may also be used to describe other
problems that interfere with sexual intercourse and reproduction, such as
lack of sexual desire and problems with ejaculation or orgasm. The term
"treatment or prevention of impotence includes, but is not limited to
impotence that results as a result of damage to nerves, arteries, smooth
muscles, and fibrous tissues, or as a result of disease, such as, but not
limited to, diabetes, kidney disease, chronic alcoholism, multiple
sclerosis, atherosclerosis, vascular disease, and neurologic disease.

[0206] As used herein, "treatment or prevention of hypertension"
encompasses treating or preventing blood flow through the vessels at a
greater than normal force, which strains the heart; harms the arteries;
and increases the risk of heart attack, stroke, and kidney problems. The
term hypertension includes, but is not limited to, cardiovascular
disease, essential hypertension, hyperpiesia, hyperpiesis, malignant
hypertension, secondary hypertension, or white-coat hypertension.

[0207] As used herein, "treatment or prevention of inflammation"
encompasses treating or preventing inflammation diseases including, but
not limited to, chronic inflammatory disorders of the joints including
arthritis, e.g., rheumatoid arthritis and osteoarthritis; respiratory
distress syndrome, inflammatory bowel diseases such as ileitis,
ulcerative colitis and Crohn's disease; and inflammatory lung disorders
such as asthma and chronic obstructive airway disease, inflammatory
disorders of the eye such as corneal dystrophy, trachoma, onchocerciasis,
uveitis, sympathetic ophthalmitis, and endophthalmitis; inflammatory
disorders of the gum, e.g., periodontitis and gingivitis; tuberculosis;
leprosy; inflammatory diseases of the kidney including glomerulonephritis
and nephrosis; inflammatory disorders of the skin including acne,
sclerodermatitis, psoriasis, eczema, photoaging and wrinkles;
inflammatory diseases of the central nervous system, including
AIDS-related neurodegeneration, stroke, neurotrauma, Alzheimer's disease,
encephalomyelitis and viral or autoimmune encephalitis; autoimmune
diseases including thiazolidinedione often has toxic side effects.
Accordingly, in a preferred embodiment of the present invention, when a
composition of the invention is administered in combination with a PPAR
agonist, the dosage of the PPAR agonist is below that which is
accompanied by toxic side effects.

[0208] The present compositions can also be administered together with a
bile acid binding resin. Bile acid binding resins for use in combination
with the compounds and compositions of the invention include but are not
limited to cholestyramine and colestipol hydrochloride. The present
compositions can also be administered together with niacin or nicotinic
acid. The present compositions can also be administered together with a
RXR agonist. RXR agonists for use in combination with the compounds of
the invention include but are not limited to LG 100268, LGD 1069, 9-cis
retinoic acid, 2 (1 (3,5,5,8,8 pentamethyl 5,6,7,8 tetrahydro 2
naphthyl)cyclopropyl)pyridine 5 carboxylic acid, or 4 ((3,5,5,8,8
pentamethyl 5,6,7,8 tetrahydro 2 naphthyl)2 carbonyl)benzoic acid. The
present compositions can also be administered together with an
anti-obesity drug. Anti-obesity drugs for use in combination with the
compounds of the invention include but are not limited to
β-adrenergic receptor agonists, preferably β-3 receptor
agonists, fenfluramine, dexfenfluramine, sibutramine, bupropion,
fluoxetine, and phentermine. The present compositions can also be
administered together with a hormone. Hormones for use in combination
with the compounds of the invention include but are not limited to
thyroid hormone, estrogen and insulin. Preferred insulins include but are
not limited to injectable insulin, transdermal insulin, inhaled insulin,
or any combination thereof. As an alternative to insulin, an insulin
derivative, secretagogue, sensitizer or mimetic may be used. Insulin
secretagogues for use in combination with the compounds of the invention
include but are not limited to forskolin, dibutryl cAMP or
isobutylmethylxanthine (IBMX).

[0209] The present compositions can also be administered together with a
phosphodiesterase type 5 ("PDE5") inhibitor to treat or prevent
disorders, such as but not limited to, impotence. In a particular,
embodiment the combination is a synergistic combination of a composition
of the invention and a PDE5 inhibitor.

[0210] The present compositions can also be administered together with a
tyrophostine or an analog thereof. Tyrophostines for use in combination
with the compounds of the invention include but are not limited to
tryophostine 51.

[0211] The present compositions can also be administered together with
sulfonylurea-based drugs. Sulfonylurea-based drugs for use in combination
with the compounds of the invention include, but are not limited to,
glisoxepid, glyburide, acetohexamide, chlorpropamide, glibornuride,
tollutamide, tolazamide, glipizide, gliclazide, gliquidone, glyhexamide,
phenbutamide, and tolcyclamide. The present compositions can also be
administered together with a biguanide. Biguanides for use in combination
with the compounds of the invention include but are not limited to
metformin, phenformin and buformin.

[0212] The present compositions can also be administered together with an
a-glucosidase inhibitor. α-glucosidase inhibitors for use in
combination with the compounds of the invention include but are not
limited to acarbose and miglitol.

[0213] The present compositions can also be administered together with an
apo A-I agonist. In one embodiment, the apo A-I agonist is the Milano
form of apo A-I (apo A-IM). In a preferred mode of the embodiment, the
apo A-IM for administration in conjunction with the compounds of the
invention is produced by the method of U.S. Pat. No. 5,721,114 to
Abrahamsen. In a more preferred embodiment, the apo A-I agonist is a
peptide agonist. In a preferred mode of the embodiment, the apo A-I
peptide agonist for administration in conjunction with the compounds of
the invention is a peptide of U.S. Pat. No. 6,004,925 or 6,037,323 to
Dasseux.

[0214] The present compositions can also be administered together with
apolipoprotein E (apo E). In a preferred mode of the embodiment, the apoE
for administration in conjunction with the compounds of the invention is
produced by the method of U.S. Pat. No. 5,834,596 to Ageland.

[0215] In yet other embodiments, the present compositions can be
administered together with an HDL-raising drug; an HDL enhancer; or a
regulator of the apolipoprotein A-I, apolipoprotein A-IV and/or
apolipoprotein genes.

[0217] In another embodiment, the other therapeutic agent can be an
hematopoietic colony stimulating factor. Suitable hematopoietic colony
stimulating factors include, but are not limited to, filgrastim,
sargramostim, molgramostim and erythropoietin alfa.

[0220] The present invention includes methods for treating cancer,
comprising administering to an animal in need thereof an effective amount
of a Compound of the Invention and another therapeutic agent that is an
anti-cancer agent. Suitable anticancer agents include, but are not
limited to, those listed in Table 3.

[0221] In a specific embodiment, a composition of the invention further
comprises one or more chemotherapeutic agents and/or is administered
concurrently with radiation therapy. In another specific embodiment,
chemotherapy or radiation therapy is administered prior or subsequent to
administration of a present composition, preferably at least an hour,
five hours, 12 hours, a day, a week, a month, more preferably several
months (e.g., up to three months), subsequent to administration of a
composition of the invention.

[0222] In other embodiments, the invention provides methods for treating
or preventing cancer, comprising administering to an animal in need
thereof an effective amount of a Compound of the Invention and a
chemotherapeutic agent. In one embodiment the chemotherapeutic agent is
that with which treatment of the cancer has not been found to be
refractory. In another embodiment, the chemotherapeutic agent is that
with which the treatment of cancer has been found to be refractory. The
Compounds of the Invention can be administered to an animal that has also
undergone surgery as treatment for the cancer.

[0223] In one embodiment, the additional method of treatment is radiation
therapy.

[0224] In a specific embodiment, the Compound of the Invention is
administered concurrently with the chemotherapeutic agent or with
radiation therapy. In another specific embodiment, the chemotherapeutic
agent or radiation therapy is administered prior or subsequent to
administration of a Compound of the Invention, preferably at least an
hour, five hours, 12 hours, a day, a week, a month, more preferably
several months (e.g., up to three months), prior or subsequent to
administration of a Compound of the Invention.

[0225] A chemotherapeutic agent can be administered over a series of
sessions, any one or a combination of the chemotherapeutic agents listed
in Table 3 can be administered. With respect to radiation, any radiation
therapy protocol can be used depending upon the type of cancer to be
treated. For example, but not by way of limitation, x-ray radiation can
be administered; in particular, high-energy megavoltage (radiation of
greater that 1 MeV energy) can be used for deep tumors, and electron beam
and orthovoltage x-ray radiation can be used for skin cancers. Gamma-ray
emitting radioisotopes, such as radioactive isotopes of radium, cobalt
and other elements, can also be administered.

[0226] Additionally, the invention provides methods of treatment of cancer
with a Compound of the Invention as an alternative to chemotherapy or
radiation therapy where the chemotherapy or the radiation therapy has
proven or can prove too toxic, e.g., results in unacceptable or
unbearable side effects, for the subject being treated. The animal being
treated can, optionally, be treated with another cancer treatment such as
surgery, radiation therapy or chemotherapy, depending on which treatment
is found to be acceptable or bearable.

[0227] The Compounds of the Invention can also be used in an in vitro or
ex vivo fashion, such as for the treatment of certain cancers, including,
but not limited to leukemias and lymphomas, such treatment involving
autologous stem cell transplants. This can involve a multi-step process
in which the animal's autologous hematopoietic stem cells are harvested
and purged of all cancer cells, the patient's remaining bone-marrow cell
population is then eradicated via the administration of a high dose of a
Compound of the Invention with or without accompanying high dose
radiation therapy, and the stem cell graft is infused back into the
animal. Supportive care is then provided while bone marrow function is
restored and the animal recovers.

5.4 Surgical Uses

[0228] Cardiovascular diseases such as atherosclerosis often require
surgical procedures such as angioplasty. Angioplasty is often accompanied
by the placement of a reinforcing a metallic tube shaped structure known
as a "stent" into a damaged coronary artery. For more serious conditions,
open heart surgery such as coronary bypass surgery may be required. These
surgical procedures entail using invasive surgical devices and/or
implants, and are associated with a high risk of restenosis and
thrombosis. Accordingly, the compounds and compositions of the invention
may be used as coatings on surgical devices (e.g., catheters) and
implants (e.g., stents) to reduce the risk of restenosis and thrombosis
associated with invasive procedures used in the treatment of
cardiovascular diseases.

5.5 Veterinary and Livestock Uses

[0229] A composition of the invention can be administered to a non-human
animal for a veterinary use for treating or preventing a disease or
disorder disclosed herein.

[0230] In a specific embodiment, the non-human animal is a household pet.
In another specific embodiment, the non-human animal is a livestock
animal. In a preferred embodiment, the non-human animal is a mammal, most
preferably a cow, horse, sheep, pig, cat, dog, mouse, rat, rabbit, or
guinea pig. In another preferred embodiment, the non-human animal is a
fowl species, most preferably a chicken, turkey, duck, goose, or quail.

[0231] In addition to veterinary uses, the compounds and compositions of
the invention can be used to reduce the fat content of livestock to
produce leaner meats. Alternatively, the compounds and compositions of
the invention can be used to reduce the cholesterol content of eggs by
administering the compounds to a chicken, quail, or duck hen. For
non-human animal uses, the compounds and compositions of the invention
can be administered via the animals' feed or orally as a drench
composition.

[0233] The invention provides methods of treatment and prophylaxis by
administration to a patient of a therapeutically effective amount of a
compound or a composition comprising a compound of the invention. The
patient is an animal, including, but not limited, to an animal such a
cow, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat,
rabbit, guinea pig, etc., and is more preferably a mammal, and most
preferably a human.

[0234] The compounds and compositions of the invention, are preferably
administered orally. The compounds and compositions of the invention may
also be administered by any other convenient route, for example, by
intravenous infusion or bolus injection, by absorption through epithelial
or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal
mucosa, etc.) and may be administered together with another biologically
active agent. Administration can be systemic or local. Various delivery
systems are known, e.g., encapsulation in liposomes, microparticles,
microcapsules, capsules, etc., and can be used to administer a compound
of the invention. In certain embodiments, more than one compound of the
invention is administered to a patient. Methods of administration include
but are not limited to intradermal, intramuscular, intraperitoneal,
intravenous, subcutaneous, intranasal, epidural, oral, sublingual,
intranasal, intracerebral, intravaginal, transdermal, rectally, by
inhalation, or topically, particularly to the ears, nose, eyes, or skin.
The preferred mode of administration is left to the discretion of the
practitioner, and will depend in-part upon the site of the medical
condition. In most instances, administration will result in the release
of the compounds of the invention into the bloodstream.

[0235] In specific embodiments, it may be desirable to administer one or
more compounds of the invention locally to the area in need of treatment.
This may be achieved, for example, and not by way of limitation, by local
infusion during surgery, topical application, e.g., in conjunction with a
wound dressing after surgery, by injection, by means of a catheter, by
means of a suppository, or by means of an implant, said implant being of
a porous, non-porous, or gelatinous material, including membranes, such
as sialastic membranes, or fibers. In one embodiment, administration can
be by direct injection at the site (or former site) of an atherosclerotic
plaque tissue.

[0236] In certain embodiments, for example, for the treatment of
Alzheimer's Disease, it may be desirable to introduce one or more
compounds of the invention into the central nervous system by any
suitable route, including intraventricular, intrathecal and epidural
injection. Intraventricular injection may be facilitated by an
intraventricular catheter, for example, attached to a reservoir, such as
an Ommaya reservoir.

[0237] Pulmonary administration can also be employed, e.g., by use of an
inhaler or nebulizer, and formulation with an aerosolizing agent, or via
perfusion in a fluorocarbon or synthetic pulmonary surfactant. In certain
embodiments, the compounds of the invention can be formulated as a
suppository, with traditional binders and vehicles such as triglycerides.

[0238] In another embodiment, the compounds and compositions of the
invention can be delivered in a vesicle, in particular a liposome (see
Langer, 1990, Science 249:1527 1533; Treat et al., in Liposomes in the
Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler
(eds.), Liss, New York, pp. 353 365 (1989); Lopez Berestein, ibid., pp.
317 327; see generally ibid.).

[0240] The present compositions will contain a therapeutically effective
amount of a compound of the invention, optionally more than one compound
of the invention, preferably in purified form, together with a suitable
amount of a pharmaceutically acceptable vehicle so as to provide the form
for proper administration to the patient.

[0241] In a specific embodiment, the term "pharmaceutically acceptable"
means approved by a regulatory agency of the Federal or a state
government or listed in the U.S. Pharmacopeia or other generally
recognized pharmacopeia for use in animals, and more particularly in
humans. The term "vehicle" refers to a diluent, adjuvant, excipient, or
carrier with which a compound of the invention is administered. Such
pharmaceutical vehicles can be liquids, such as water and oils, including
those of petroleum, animal, vegetable or synthetic origin, such as peanut
oil, soybean oil, mineral oil, sesame oil and the like. The
pharmaceutical vehicles can be saline, gum acacia, gelatin, starch paste,
talc, keratin, colloidal silica, urea, and the like. In addition,
auxiliary, stabilizing, thickening, lubricating and coloring agents may
be used. When administered to a patient, the compounds and compositions
of the invention and pharmaceutically acceptable vehicles are preferably
sterile. Water is a preferred vehicle when the compound of the invention
is administered intravenously. Saline solutions and aqueous dextrose and
glycerol solutions can also be employed as liquid vehicles, particularly
for injectable solutions. Suitable pharmaceutical vehicles also include
excipients such as starch, glucose, lactose, sucrose, gelatin, malt,
rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate,
talc, sodium chloride, dried skim milk, glycerol, propylene, glycol,
water, ethanol and the like. The present compositions, if desired, can
also contain minor amounts of wetting or emulsifying agents, or pH
buffering agents.

[0242] The present compositions can take the form of solutions,
suspensions, emulsion, tablets, pills, pellets, capsules, capsules
containing liquids, powders, sustained-release formulations,
suppositories, emulsions, aerosols, sprays, suspensions, or any other
form suitable for use. In one embodiment, the pharmaceutically acceptable
vehicle is a capsule (see e.g., U.S. Pat. No. 5,698,155). Other examples
of suitable pharmaceutical vehicles are described in "Remington's
Pharmaceutical Sciences" by E. W. Martin.

[0243] In a preferred embodiment, the compounds and compositions of the
invention are formulated in accordance with routine procedures as a
pharmaceutical composition adapted for intravenous administration to
human beings. Typically, compounds and compositions of the invention for
intravenous administration are solutions in sterile isotonic aqueous
buffer. Where necessary, the compositions may also include a solubilizing
agent. Compositions for intravenous administration may optionally include
a local anesthetic such as lignocaine to ease pain at the site of the
injection. Generally, the ingredients are supplied either separately or
mixed together in unit dosage form, for example, as a dry lyophilized
powder or water free concentrate in a hermetically sealed container such
as an ampoule or sachette indicating the quantity of active agent. Where
the compound of the invention is to be administered by intravenous
infusion, it can be dispensed, for example, with an infusion bottle
containing sterile pharmaceutical grade water or saline. Where the
compound of the invention is administered by injection, an ampoule of
sterile water for injection or saline can be provided so that the
ingredients may be mixed prior to administration.

[0244] Compounds and compositions of the invention for oral delivery may
be in the form of tablets, lozenges, aqueous or oily suspensions,
granules, powders, emulsions, capsules, syrups, or elixirs. Compounds and
compositions of the invention for oral delivery can also be formulated in
foods and food mixes. Orally administered compositions may contain one or
more optionally agents, for example, sweetening agents such as fructose,
aspartame or saccharin; flavoring agents such as peppermint, oil of
wintergreen, or cherry; coloring agents; and preserving agents, to
provide a pharmaceutically palatable preparation. Moreover, where in
tablet or pill form, the compositions may be coated to delay
disintegration and absorption in the gastrointestinal tract thereby
providing a sustained action over an extended period of time. Selectively
permeable membranes surrounding an osmotically active driving compound
are also suitable for orally administered compounds and compositions of
the invention. In these later platforms, fluid from the environment
surrounding the capsule is imbibed by the driving compound, which swells
to displace the agent or agent composition through an aperture. These
delivery platforms can provide an essentially zero order delivery profile
as opposed to the spiked profiles of immediate release formulations. A
time delay material such as glycerol monostearate or glycerol stearate
may also be used. Oral compositions can include standard vehicles such as
mannitol, lactose, starch, magnesium stearate, sodium saccharine,
cellulose, magnesium carbonate, etc. Such vehicles are preferably of
pharmaceutical grade.

[0245] The amount of a compound of the invention that will be effective in
the treatment of a particular disorder or condition disclosed herein will
depend on the nature of the disorder or condition, and can be determined
by standard clinical techniques. In addition, in vitro or in vivo assays
may optionally be employed to help identify optimal dosage ranges. The
precise dose to be employed in the compositions will also depend on the
route of administration, and the seriousness of the disease or disorder,
and should be decided according to the judgment of the practitioner and
each patient's circumstances. However, suitable dosage ranges for oral
administration are generally about 0.001 milligram to 2000 milligrams of
a compound of the invention per kilogram body weight. In specific
preferred embodiments of the invention, the oral dose is 0.01 milligram
to 1000 milligrams per kilogram body weight, more preferably 0.1
milligram to 100 milligrams per kilogram body weight, more preferably 0.5
milligram to 25 milligrams per kilogram body weight, and yet more
preferably 1 milligram to 10 milligrams per kilogram body weight. In a
most preferred embodiment, the oral dose is 5 milligrams of a compound of
the invention per kilogram body weight. The dosage amounts described
herein refer to total amounts administered; that is, if more than one
compound of the invention is administered, the preferred dosages
correspond to the total amount of the compounds of the invention
administered. Oral compositions preferably contain 10% to 95% active
ingredient by weight.

[0246] Suitable dosage ranges for intravenous (i.v.) administration are
0.01 milligram to 1000 milligrams per kilogram body weight, 0.1 milligram
to 350 milligrams per kilogram body weight, and 1 milligram to 100
milligrams per kilogram body weight. Suitable dosage ranges for
intranasal administration are generally about 0.01 pg/kg body weight to 1
mg/kg body weight. Suppositories generally contain 0.01 milligram to 50
milligrams of a compound of the invention per kilogram body weight and
comprise active ingredient in the range of 0.5% to 10% by weight.
Recommended dosages for intradermal, intramuscular, intraperitoneal,
subcutaneous, epidural, sublingual, intracerebral, intravaginal,
transdermal administration or administration by inhalation are in the
range of 0.001 milligram to 200 milligrams per kilogram of body weight.
Suitable doses of the compounds of the invention for topical
administration are in the range of 0.001 milligram to 1 milligram,
depending on the area to which the compound is administered. Effective
doses may be extrapolated from dose-response curves derived from in vitro
or animal model test systems. Such animal models and systems are well
known in the art.

[0247] The invention also provides pharmaceutical packs or kits comprising
one or more containers filled with one or more compounds of the
invention. Optionally associated with such container(s) can be a notice
in the form prescribed by a governmental agency regulating the
manufacture, use or sale of pharmaceuticals or biological products, which
notice reflects approval by the agency of manufacture, use or sale for
human administration. In a certain embodiment, the kit contains more than
one compound of the invention. In another embodiment, the kit comprises a
compound of the invention and another lipid-mediating compound, including
but not limited to a statin, a thiazolidinedione, or a fibrate.

[0248] The compounds of the invention are preferably assayed in vitro and
in vivo, for the desired therapeutic or prophylactic activity, prior to
use in humans. For example, in vitro assays can be used to determine
whether administration of a specific compound of the invention or a
combination of compounds of the invention is preferred for lowering fatty
acid synthesis. The compounds and compositions of the invention may also
be demonstrated to be effective and safe using animal model systems.

[0249] Other methods will be known to the skilled artisan and are within
the scope of the invention.

[0250] The following examples are provided by way of illustration and not
limitation.

[0285] In a number of different experiments, illustrative compounds of the
invention are administered daily at a dose of up to 100 mg/kg to chow fed
obese female Zucker rats for fourteen days in the morning by oral gavage
in 1.5% carboxymethylcellulose/0.2% Tween 20 or 20% ethanol/80%
polyethylene glycol (dosing vehicles). Animals are weighed daily. Animals
are allowed free access to rodent chow and water throughout the study
except on days of blood sampling where food is restricted for six hours
prior to blood sampling. Blood glucose is determined after the 6 hour
fast in the afternoon without anesthesia from a tail vein. Serum is also
prepared from pretreatment blood samples subsequently obtained from the
orbital venous plexus (with O2/CO2 anesthesia) and following
the fourteenth dose at sacrifice from the heart following
O2/CO2 anesthesia. Serums are assayed for lipoprotein
cholesterol profiles, triglycerides, total cholesterol, Non-HDL
cholesterol, HDL cholesterol, the ratio of HDL cholesterol to that of
Non-HDL cholesterol, insulin, non-esterified fatty acids, and
beta-hydroxy butyric acid. The percent body weight gain and the ratio of
liver to body weight is also determined. These are shown as absolute
values or as a percent change of the pretreatment values in Table 1.

[0287] The present invention is not to be limited in scope by the specific
embodiments disclosed in the examples which are intended as illustrations
of a few aspects of the invention and any embodiments which are
functionally equivalent are within the scope of this invention. Indeed,
various modifications of the invention in addition to those shown and
described herein will become apparent to those skilled in the art and are
intended to fall within the appended claims.

Patent applications by Jean-Louis H. Dasseux, Toulouse FR

Patent applications in class Ring sulfur in the bicyclo ring system

Patent applications in all subclasses Ring sulfur in the bicyclo ring system